Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. The overwhelming cause of severe vision loss in these patients is choroidal neovascularization (CNV), the growth of abnormal blood vessels beneath the retina. The mechanisms responsible for this process have been deduced to angiogenesis, the sprouting of new blood vessels from pre-existing vasculature, and vasculogenesis, the recruitment, proliferation and incorporation of bone marrow-derived progenitor cells into nascent vasculature. Vascular endothelial growth factor-A (VEGF-A) is a critical mediator in both these pathways and is the target for many FDA approved therapies for CNV. Using the mouse model of laser-induced CNV, we recently discovered a paradoxical effect whereby both endogenous and exogenous VEGF-A suppressed CNV during the acute phase after laser-injury, whereas before injury they enhanced CNV consistent with dogma. We determined that the matricellular protein SPARC/osteonectin constitutively interacts with VEGF-A and prevents it from activating VEGF receptor (VEGFR)-1. Because SPARC levels decline transiently after injury, VEGF-A activates an anti-angiogenic pathway through VEGFR-1 binding and subsequent dephosphorylation of VEGFR-2, the principal signaling receptor that promotes neovascularization. VEGF-A also downregulated the expression of monocyte chemoattractant protein-1 (Ccl-2), which suppressed cell-mediated inflammation and subsequent CNV. The molecular basis of the vexing macular predilection for CNV in humans is unknown; however the spatial confinement of SPARC in the macula of monkey retina is intriguing as a potential underpinning for this phenomenon. The specific aims of this proposal are to further define the interaction of SPARC and VEGF-A in experimental CNV, determine the precise anti-angiogenic and anti-vasculogenic mechanisms of VEGF-A induced CNV suppression, evaluate the efficacy of modulating SPARC in a non-human primate model of CNV, and define the expression and activity profiles of SPARC and VEGF-A and its receptors in human retina and choroid. Our long term goal is to fully characterize the SPARC-VEGF-A pathway in CNV and identify novel targets for the treatment of this blinding condition which constitutes nothing short of a public health epidemic. [unreadable] [unreadable] [unreadable]